1. Wilms’ Tumor – Indications for Radiotherapy
Tasha McDonald M.D.
Parag Sanghvi M.D.
Department of Radiation Medicine

2. Treatment Based on cooperative group philosophies 3 major groups
National Wilm’s Tumor Study (NWTS)
Societe Internationale d’Oncologie Pediatrique (SIOP)
United Kingdom Children’s Cancer Study Group (UKCCSG)

3. NWTS Strategy
Assess local extent, degree of anaplasia, presence of unusual histology, presence of LN involvement
Assess without preoperative treatment
Gather prognostic clues
Avoid misdiagnosis
Customize therapy

4. NWTS 1 – 4 Schema

5. NWTS 1 (1969 – 1974) D’Angio GJ, et al. Cancer 64:349-360, 1989
Is postoperative radiotherapy necessary in group I disease?
Is single agent chemo with vincristine or actinomycin D equivalent to combining these drugs for group II and III disease?
Is preoperative vincristine of value in group IV disease?
Radiation doses adjusted for age
Birth – 18 mo 18 to 24 Gy
18 – 30 mo 24 to 30 Gy
mo 30 to 35 Gy
41 mo or older 35 – 40 Gy

6. NWTS 1 Results Post-op XRT not needed for group I <2 yo
Actino/Vincr better than either agent alone for group II and III
Preop vincristine not useful in group IV
RFS for group I patients >2 yo w/Actino +RT 84%
RFS for group II/III w/Actino/Vincr/XRT 84%

7. NWTS 1 Results 2-year relapse free survival Poor prognostic factors
Favorable histology 89%
Unfavorable histology 29%
Poor prognostic factors
Large tumor size
Lymph node involvement
Age >2 years
No radiation dose response between Gy
Delays of up to 10 days for post-op tx found acceptable
Whole abdominal XRT not necessary for tumor spills confined to the flank

8. NWTS
Can Vincr & Actino substitute for RT in older children with Group I disease?
Are protracted periods of adjuvant Vincr & Actino helpful for Groups II – IV?
Is addition of Adriamycin to Actino and Vincr of value in Groups II – IV?

9. NWTS 2 Results Vincr & Actino can substitute for RT in Group I disease
6 months = 15 months Actino/Vincr for Group I
Addition of Adria to Actino/Vincr/XRT for Groups II-IV provided benefit
Worse 2-year survival for lymph node + (54% vs 82%) and patients with unfavorable histology (54% vs 90%)

10. NWTS 3 1979 – 1985 Green DM, et al. Pediatr Clin North Am 38:475-488, 1991
Patients stratified by Stage instead of Group
FH & UH incorporated in the treatment algorithm
Five questions
Can duration of chemotherapy shortened for Stage I FH?
Can RT be eliminated for Stage II FH?
What is the minimum effective RT dose for Stage III FH?
Is Adriamycin clearly beneficial and necessary for Stages II & III FH?
Will Cyclophosphamide improve survival in Stages I – IV UH and Stage IV FH?
Stage I FH: Vinc/Actino (no RT) 24 vs 10 weeks
Stage II FH: 3 vs. 2 drugs (? Adriamycin necessity), +/- XRT 20 Gy
Stage III FH: 10 vs. 20 Gy, 3 vs. 2 drugs
Stage IV FH and all UH: XRT/3 drugs +/- cytoxan

11. NWTS 3 Stage I FH: Vinc/Actino (no RT) 24 vs 10 weeks
Stage II FH: 3 vs. 2 drugs (? Adriamycin necessity), +/- XRT 20 Gy
Stage III FH: 10 vs. 20 Gy, 3 vs. 2 drugs
Stage IV FH and all UH: XRT/3 drugs +/- cyclophosphamide

12. NWTS 3 Results Stage I: 10 wks vs. 6 months equivalent (VA)
4-year RFS 89% OS 96%
Stage II: no difference between 2 or 3 drugs with or without XRT
4-year RFS 87% OS 91%
Stage III: No stat sig difference in abdominal relapse between 10 and 20 Gy, trend favored use of Adriamycin or 20 Gy
4-year RFS 82% OS 91%

13. NWTS 3 Results
Stage IV: 4 drugs equal to 3 drugs (both include abdominal and lung XRT)
4-year RFS 79% OS 80%
Anaplasia
4 drugs better than 3 drugs for stage II-IV
Clear cell sarcoma patients had trend toward improvement with Cyclophosphamide
25% OS for rhabdoid in both arms

14. NWTS
Addressed issues of minimization of therapy and customization by Stage & Histology
Evaluate the role of pulse dosed chemotherapy

15. NWTS 4 Schema

16. NWTS 4 Results
Pulse–intensive chemotherapy feasible, produce less hematologic toxicity and allow for increased drug dose-intensity
Cost analysis showed savings of $790,000 a year in the US if all Wilms’ patients were treated on pulse-intensive regimens

17. NWTS 5 Schema

18. NWTS 5 Results LOH 1p / 16q
LOH 1p associated with significantly worse RFS in Stage II but not Stage III/IV
Suggests that adverse effects of LOH 1p can be overcome by more aggressive chemotherapy

19. NWTS 5 Selected Results - FH
Stage I FH 4 y RFS 92% OS 98%
Stage II FH 4 y RFS 83% OS 92%
Stage III FH (included RT) 4 y RFS 85.3% OS 93.9%
Stage IV FH 4 y EFS 74.6% (most of these patients had lung mets and received pulmonary RT)

20. NWTS 5 Selected Results UH
Diffuse Anaplasia 2 y EFS
Stage I 64.3 %
Stage II 79.5%
Stage III 62.7%
Stage IV 33.6%
CCSK
Stage I –IV 4y RFS 77.6%
6/9 Stage IV patients relapsed
Rhabdoid Tumors
Stage I 50%
Stage II 33.3%
Stage III 33.3%
Stage IV 21.4 %
Stage V 0%

21. Selected Results from NWTS 5
High rate relapse for Stage I patients with diffuse anaplasia (10/29 patients, 5 deaths); 4 y/o RFS 64.3 %
High rate of relapse for Stage I focal anaplasia (3/9 patients, 2 deaths)
Improved control of Stage I CCSK patients 4 y/o RFS 100% (0/14 patients)
There was a subset of “very low risk” patients - < 2 years, Stage I FH, <550 g who were initially assigned to NO adjuvant therapy; interim analysis showed 2 y EFS 86.5% which was lower than expected; this arm was subsequently closed

22. Current Protocols AREN 0532
FH Stage I through FH Stage III Standard Risk

23. AREN 0533 / AREN 0321 AREN 0533 AREN 0321 FH Stage III High Risk
FH Stage IV
AREN 0321
UH Wilms’
Clear Cell Sarcoma of the Kidney
Rhabdoid Tumor
RCC

24. AREN 0533
Eliminate pulmonary
RT in Stage IV FH Rapid Responders

25. Who gets XRT today Favorable Histology Anaplastic Histology
Stage I & II NO RT
Stage III RT to Tumor Bed (10.8 Gy) or Whole Abdomen RT (10.5 Gy**)
Stage IV RT to tumor bed or Whole abdomen if the primary tumor would have otherwise qualified as Stage III; RT to metastases
Stage V – Stage each side independently; if Stage III then treat as above
Anaplastic Histology
Stage I Localized RT to tumor bed (10.8 Gy)
Stage II – Localized RT to tumor bed (10.8 Gy)
Stage III – Localized RT to tumor bed (19.8 Gy) or Whole Abdomen ( Gy)
Stage IV – If primary tumor would qualify as Stage I then no RT; if Stage II or III as above; RT to metastases

26. Who gets XRT today Clear Cell Sarcoma of the Kidney
Stage I – NO RT except for if LN sampling or pathology review not performed ( Gy)
Stage II – Localized RT to tumor bed (10.8 Gy)
Stage III – Localized or Whole Abdomen** akin to FH Stage III (10.8 Gy/10.5 Gy**)
Stage IV – Treat primary tumor again based on Stage; treat metastases

27. Who gets XRT today? Rhabdoid Tumor Stage I – Localized RT to tumor bed
Stage II – Localized RT to tumor bed
Stage III – Localized or Whole Abdomen** akin to FH Stage III
Stage IV – Treat primary tumor again based on Stage; treat metastases
All stages get RT!!! Dose is age-dependent
<12 months 10.8 Gy
≥ 12 months 19.8 Gy / Gy**

28. M.K.
20 mo girl with Rhabdoid Tumor of the kidney with presumed metastases to bone and lungs; intraop tumor spillage
Dx: 4/3/07
Treated per protocol AREN0321
Recommendations would be for RT
Whole lung to 12 Gy
Femur met to 25.2 Gy
Whole abdomen to Gy

29. Current Radiotherapy Guidelines Tumor Bed/Flank RT
XRT should start by day 10 post-op (surgery day is day 1) but no later than day 14
Fraction size is 1.8 Gy unless large field
Radiation dose for flank/tumor bed is 10.8 Gy except
Stage III Diffuse Anaplasia & Rhabdoid Tumor 19.8 Gy
Boost gross residual disease with additional Gy
Limit dose to more than ½ of uninvolved liver to 19.8 Gy

30. Current Radiotherapy Guidelines Tumor Bed/Flank RT
Dose to more than 1/3 of the contralateral kidney or residual kidney for bilateral Wilms’ should not exceed 14.4 Gy
Tumor Bed is determined by pre-operative CT
Includes kidney + tumor + 1 cm margin
Treat all of the vertebral body to avoid scoliosis
Recommend AP/PA for fields; IMRT allowed for boost

31. Treatment Fields - Flank

32. Treatment Fields – Whole Abdomen
Used for patients with diffuse peritoneal seeding, gross tumor spillage within the abdominal cavity during surgery or pre-op intraperitoneal rupture
Portals
Superior – 1 cm above diaphragm
Inferior – Bottom of obturator foramen
Lateral – 1 cm beyond lateral abdominal wall
Shield femoral heads
Total Dose 10.5 Gy (1.5 Gy / fx) except for patients with Diffuse Anaplasia or Rhabdoid Tumors (19.5 – 21 Gy)
If need to boost for diffuse unresectable peritoneal implants then can treat whole abdomen to 21 Gy; shield remaining kidney to not get more than 14.4 Gy

33. Treatment Fields – Whole Abdomen

34. A.M. 3 yo 10 month girl Presented with one day of severe abd pain
Outside ED: UA + blood, Tx to OHSU ED
U/S 12 x 12 cm abd mass
CT c/a/p: 12 x 12 x 13.6 cm RUQ mass arising from upper pole of kidney with evidence of tumor rupture; no evidence of mets
Admitted to DCH

35. A.M.

36. A.M.
4/6/07: Taken to OR for attempted resection but biopsy only secondary to size of tumor; then developed compartment syndrome
Path: favorable histology Wilm’s
4/9/07: Resection with spillage of tumor into abdomen; + bx’s of diaphragm, liver, adrenal and rectocaval fibrous tissue
STAGE III Favorable Histology Wilm’s

37. A.M. Treatment Resection: 4/9/07 Chemotherapy RT: 4/18/07
Tumor spillage
Chemotherapy
DD4A
RT: 4/18/07
Whole Abdomen
AP:PA
Dose: 1050 cGy (150 cGy x 7)

38. A.M. DRR

39. A.M. DVH

40. Current Radiotherapy Guidelines – Lung Irradiation
AREN 0533 allows for omission of Lung RT in FH patients who achieve CR with 3 drug chemotherapy (based on CT scan at Week 6)
Whole Lung XRT for patients with CXR & CT defined pulmonary metastases is 12 Gy / 8 fx (1.5 Gy /fx); 10.5 Gy if < 12 months old
Localized foci of lung disease persisting 2 weeks after 12 Gy can be excised or given additional 7.5 Gy
Treat both lungs regardless of the number or location of visible metastases
Patients with CT only pulmonary mets – at the discretion of the treating institution

41. Current Radiotherapy Guidelines – Lung Irradiation
Treatment Fields
Superior border – Above the Clavicles
Inferior border - Approximately to L1
Caution with lung boosts; upto 10% rate of pneumonopathy in patients who received 14 Gy whole lung RT or large volume RT
In infants < 18 months, trial of chemotherapy alone is suggested; if resolution of lung mets does not occur within 4 weeks of therapy; then give 9 Gy to both lungs with a single 1.5 Gy boost to specific nodules

42. Treatment Fields - Lungs

43. Pulmonary RT
Rationale behind omitting upfront pulmonary RT comes from several studies
SIOP 9
Stage IV patients with pre-op chemotherapy
57/59 patients had lung metastases; 56 had FH
40/59 patients had CR in the lung to chemotherapy or additional metastatectomy
In these 40 patients, 4 y RFS was 67.5% and OS was 87.5% 70% of these patients were spared whole – lung irradiation
When sub group analysis done by histology; in FH OS was 82.9%

44. CT only Pulmonary Metastases – NWTS 4 & 5
In NWTS 4& 5 pulmonary mets were defined as presence of nodules on CXR
There were 171 patients with CT only detected mets but not CXR
29 were Stage I or II and received Vincr + Actino D  5 y EFS 54%
58 were Stage III and received Vincr + Actino D + Adriamycin  5 y EFS 81%
84 were Stage IV and majority received pulmonary XRT  5 y EFS 78%

45. CT only Pulmonary Metastases
Patients who received Lung XRT had 1 pulmonary relapse, 1 pulmonary progression and 5 toxic deaths (2 attributed to pulmonary RT)
Patients who did not receive Lung XRT had 6 pulmonary relapses; no toxic deaths

46. C.H. 3 yo girl Presented with one week of fussiness, abdominal pain
Mom palpated mass in abdomen
Saw PCP-direct admit to DCH
U/S abd and CT abd showed Rt renal mass with IVC involvement
CXR/CT chest: multiple pulmonary nodules

47. C.H.

48. C.H.
Surgery on 4/20/07: Complete resection/ Rt nephrectomy with minimal tumor spillage confined to the renal hilum
Dx: Stage IV favorable histology Wilm’s
Chemo: per NWTS-5, regimen DD4A
RT:
Whole lung/Rt flank began on 4/30/07
AP:PA
1200 cGy (150 cGy x 8 fx)
Will get CT chest 2 weeks out (5/24) and if persistent bulky disease may boost with 750 cGy

49. Hicks DRR

50. Hicks DVH

51. Current Radiotherapy Guidelines - Metastases
Liver
Use RT only if lesions unresectable because of location or extent
Tumor + 2 cm margin; 1.8 Gy / fraction
Treat to 25.2 Gy to 39.6 Gy
Limit dose to 75 % of liver to less than 30.6 Gy
If whole liver involved, treat to 19.8 Gy
Limit dose to remaining kidney to 14.4 Gy with a posterior block

52. Current Radiotherapy Guidelines - Metastases
Brain
Whole Brain XRT to 21.6 Gy then boost of 10.8 Gy (1.8 Gy/fx)
Bone
25.2 Gy
Entire bone does not need to be treated
3 cm margin
Lymph Node (Not Surgically removed)
19.8 Gy
Adolescent and young adults (≥ 16 years) receive 30.6 Gy to sites of metastases

53. Treatment of Relapse
Children with relapsed FH Wilm’s can have a favorable outcome based on
Initial Stage
Time from initial diagnosis
Site of relapse
Previous therapy

54. Treatment of Relapse Adverse factors for relapsed Wilms’
Prior Adriamycin based chemotherapy
Relapse < 12 months from initial diagnosis
Intra-abdominal relapse after previous abdominal RT

55. Treatment of Relapse Restaging
Stage 1R – Localized Disease, completely excised
Stage 2R – Gross total resection with evidence of regional spread
Stage 3R – Residual non-hematogenous tumor present and confined to abdomen
Stage 4R – Hematogenous mets present
Stage 5R – bilateral Renal involvement

56. Treatment of Relapse – Radiotherapy Guidelines
Radiotherapy is administered to patients at site of relapse
Dose to infradiaphragmatic sites
Complete Remission after Surgery (1R/2R) who have either received no previous RT or have received 10.8 Gy
Birth – 12 months – Gy
13 months or older – 21.6 Gy
Gross Residual Disease after Surgery
Should get a boost
Total dose including boost should not exceed 30 Gy

57. Treatment of Relapse – Radiotherapy Guidelines
Dose to infradiaphragmatic sites
Total Nominal Dose (including previous RT)
<36 months – should not exceed 30.6 Gy
>36 months – should not exceed 39.6 Gy
Total Spine dose should not exceed 41.4 Gy
Total Liver dose should not exceed 30.6 Gy
Total Remaining Kidney dose should not exceed Gy

58. Treatment of Relapse – Radiotherapy Guidelines
Lung Irradiation
Complete remission & No previous RT
≤ 18 months: 9 Gy; 1.5 Gy/fx
> 18 months: 12 Gy, 1.5 Gy/fx
Gross Residual Disease after surgical resection & No previous RT
Can boost gross disease with additional 7.5 Gy
Liver, Brain, Bone mets
Follow guidelines from NWTS 5

59. L.L. 4/06 Dx with Stage I favorable histology Wilm’s at age 3
S/p complete resection Rt renal mass/nephrectomy
Chemo:
CCG 5941 protocol/regimen EE4A
18 weeks Vincr/Actino
Finished chemo 7/06
Close f/u

60. L.L. Regular F/U appt 3/14/07 Asymptomatic
Abd U/S: 5.6 cm mass in Rt renal fossa
CT abdomen: 5.9 x 4.3 cm homogeneous mass in Rt renal fossa
CT chest: no metastatic disease

61. Lawson

62. L.L. Surgery on 3/19/07: complete resection
Pathology: Recurrent favorable histology Wilm’s
Stage 1R
Chemotherapy: Vincristine, Actinomycin D per NWTS-5 relapse protocol, regimen 1
RT began 4/13/07
2160 cGy to Rt flank
180 cGy x 12 fx
AP:PA

63. L.L. DRR

64. L.L. DVH

65. T.B. 12 yo girl with hx of Stage IV Wilm’s Tumor dx in December 2003
Tx’ed with chemo (Vincr/Actino/Doxo) and RT (12 Gy to whole lung/whole abd)
8/2004: relapse with pulmonary nodules tx with carbo/etop/ifos/melphalan w/ stem cell rescue
2/06: abdominal relapse s/p resection and carbo/topotecan
2/07: 4 x 10 cm mass in left ileopsoas muscle with extension into spinal canal at T12-L1

66. T.B. Tx: Palliative RT RT to left flank 2520 cGy 180 cGy x 14 fx
Total abd dose = 3720 cGy (including RT in 2003)

67. Beach DRR

68. Acknowledgements
Dr. Carol Marquez (for teaching us everything I know about Wilms’)
Dr. Charles Thomas
Dr. Kamal Patel
Dr. Christopher Lee